This is an innovative R21 application to investigate abnormalities of protein-protein interactions in schizophrenia. It is an understatement to say that the treatment of schizo-spectrum disorders has not progressed in the past 20 years since the development of atypical antipsychotics. There is broad consensus that these newer medications do not extend the efficacy of pharmacological treatments to cognitive and negative/deficit symptoms, which lead to profound disability in persons afflicted with schizophrenia. Thus, there is a pressing need to develop a more sophisticated understanding of the pathophysiology of this illness in order to develop new treatment strategies. Converging evidence suggests that schizophrenia is a disorder of neuroplasticity, involving pathophysiological changes in synaptic function that lead to cognitive deficits. Synapses throughout the brain contain microdomains called postsynaptic densities, which are dynamic aggregations of receptor, structural, and signaling proteins. Postsynaptic densities in excitatory synapses contain ionotropic glutamate receptors, including NMDA and AMPA receptors, and multipotent scaffolding molecules, such as postsynaptic density-95 (PSD-95). PSD-95 regulates trafficking and assembly of postsynaptic density constituents via protein-protein interactions. Co-localization of receptors in the postsynaptic density via scaffolding proteins underlies molecular correlates of learning and memory, such as long-term potentiation (LTP) and long-term depression (LTD). Accumulating evidence implicates abnormalities of postsynaptic density content and function in schizophrenia, but studies on key elements of the postsynaptic density in schizophrenia have not been performed. We postulate that there are profound changes in the constituents of postsynaptic protein complexes in this illness. We specifically hypothesize that abnormalities of the PSD-95 protein-protein interactome underlie the neuroplastic defects found in chronic schizophrenia. We propose to affinity purify PSD-95 protein complexes from the dorsolateral prefrontal cortex in subjects with chronic schizophrenia (n = 20) and a control group (n = 20), and examine the PSD-95 interactome using liquid chromatography-mass spectrometry (LCMS/MS). We will follow up these studies with targeted LCMS/MS and western blot analyses to confirm changes in protein expression and concentration from our initial studies. We will use pathway analyses and network modeling to identify biological processes and upstream modulators involved in the pathophysiology of schizophrenia. Finally, we propose confirmation studies that include assessing the same dependent measures in an animal model of broken synapses, as well as antipsychotic treated rodents. This application proposes experiments that will extend our understanding of the pathophysiology of schizophrenia and identify novel substrates that may be targeted for the treatment of this often devastating illness.